ATF5 has been shown to be a critical regulator of cell proliferation and survival; however, the underlying mechanism remains largely unknown. We demonstrate here that ATF5 interacts with the transcriptional coactivator p300, which acetylates ATF5 at lysine-29 (K29), which in turn enhances the interaction between ATF5 and p300 and binding of the ATF5/p300 complex to the ATF5 response element (ARE) region of the Egr-1 promoter. ARE-bound ATF5/p300 acetylates lysine-14 (K14) of nucleosomal histone H3 at both the ARE and serum response element (SRE) of the Egr-1 promoter, which facilitates binding of extracellular signalregulated kinase (ERK)-phosphorylated Elk-1 to the SRE, activating the Egr-1 promoter. Interference of p300-dependent acetylation of ATF5 or nucleosomal histone H3 or blockade of ERK-dependent Elk-1 phosphorylation abrogates ATF5-dependent Egr-1 activation and cell proliferation and survival. These findings assign a central role for the ATF5/p300 complex in ATF5 function and suggest that coordinated actions by ATF5, p300, Elk-1, and ERK/mitogen-activated protein kinase (MAPK) are essential for ATF5-dependent Egr-1 activation and cell proliferation and survival.Uncontrolled cell proliferation and enhanced cell survival are hallmarks of cancer (22), which often results from aberrant gene expression. Transcriptional factors and their downstream genes essential for cancer progression are potential targets for cancer therapies. The activating transcription factor 5 (ATF5), a member of the ATF/CREB protein family of basic-region leucine zipper (bZIP) transcription factors (20), plays an important role in the regulation of a variety of cellular functions, including cell proliferation, survival, and stress response (18). ATF5 is highly expressed in many types of cancer, including breast cancer, glioma, neuroblastoma, medulloblastoma, thyroid follicular carcinoma, and B-cell chronic lymphocytic leukemia (18). ATF5 is upregulated by growth factors and downregulated by growth factor deprivation. Exogenous expression of ATF5 suppresses apoptosis induced by trophic withdrawal (12, 42), whereas interference of ATF5 function induces apoptosis of several types of cancer cells (2,12,39,42). On the other hand, ATF5 expression in neural progenitors and pheochromocytoma PC12 cells maintains them in a proliferative state and blocks their differentiation, whereas ATF5 loss of function in these cells causes premature differentiation (3, 4, 37), suggesting that functions of ATF5 differ from cell type to cell type. ATF5 overexpression elevates expression of Hsp27, cyclin D3, and CYP2B6 (a member of the P450 family). However, whether these genes are ATF5 targets mediating ATF5-dependent cell survival and proliferation remains unclear (18). Two recent studies indicated that Bcl-2 and the myeloid leukemia cell differentiation protein (Mcl-1), a member of the Bcl-2 family of prosurvival factors, may contribute to ATF5-promoted survival function in glioma and MCF-7 breast cancer cells; it is understood, however, that additional A...
Background: NPM1 promotes whereas ATF5 inhibits HCC proliferation; NPM1 and ATF5 are regulated in an opposite manner in normal hepatocytes and HCC. Results: NPM1 competes against HSP70 for ATF5 binding and promotes proteasome-and caspase-dependent ATF5 protein degradation. Conclusion: NPM1 is a novel ATF5-interacting protein and abrogates ATF5 function in HCC. Significance: We reveal a mechanism by which NPM1 promotes HCC proliferation and survival via regulation of ATF5.
Glioblastoma (GBM), the most common type of primary tumor in the central nervous system, is a very aggressive brain tumor with poor prognosis and a high recurrence rate. Increasing evidence suggests that human cytomegalovirus (HCMV) infection is related to GBM and leads to GBM cell growth and metastasis. MicroRNAs are important regulators in the growth and metastasis of glioblastoma. This study aimed to demonstrate the role of miR-144-3p in HCMV-positive glioblastoma. We found that, after HCMV infection, the expression of miR-144-3p decreased, whereas the expression of TOP2A increased. Bioinformatics analyses indicated that miR-144-3p directly targets the TOP2A 3′-UTR (Untranslated Region). We discovered that the overexpression of miR-144-3p downregulated the overexpression of TOP2A and inhibited the proliferation, clone formation, and invasion of HCMV-positive glioma in vitro. Taken together, these results show that miR-144-3p inhibited growth and promoted apoptosis in glioma cells by targeting TOP2A.
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